Edible water-soluble film containing a foam reducing flavoring agent

ABSTRACT

An edible water-soluble film is provided. The film includes at least one water-soluble polymer, and a foam reducing flavoring agent, wherein the film is free of added anti-foaming or defoaming agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 60/846,064 filed on Sep. 20, 2006, the contents of which areincorporated by reference.

FIELD OF THE INVENTION

This invention relates to edible water-soluble films and, morespecifically, to edible water-soluble films that include alternatives totraditional anti-foaming or defoaming agents.

BACKGROUND OF THE RELATED TECHNOLOGY

Films may be used as a delivery system to carry active ingredients suchas drugs, pharmaceuticals, and the like. However, historically films andthe process of making drug deliver systems therefrom have suffered froma number of unfavorable characteristics that have not allowed them to beused in practice.

Films that incorporate a pharmaceutically active ingredient aredisclosed in expired U.S. Pat. No. 4,136,145 to Fuchs, et al. (“Fuchs”).These films may be formed into a sheet, dried and then cut intoindividual doses. The Fuchs disclosure alleges the fabrication of auniform film, which includes the combination of water soluble polymers,surfactants, flavors, sweeteners, plastickers and drugs. These allegedlyflexible films are disclosed as being useful for oral, topical orenteral use. Examples of specific uses disclosed by Fuchs includeapplication of the films to mucosal membrane areas of the body,including the mouth, rectal, vaginal, nasal and ear areas.

Examination of films made in accordance with the process disclosed inFuchs, however, reveals that such films suffer from the aggregation orconglomeration of particles, i.e., self-aggregation, making theminherently non-uniform. This result can be attributed to Fuchs' processparameters, which although not disclosed likely include the use ofrelatively long drying times, thereby facilitating intermolecularattractive forces, convection forces, air flow and the like to form suchagglomeration.

The formation of agglomerates randomly distributes the film componentsand any active present as well. When large dosages are involved, a smallchange in the dimensions of the film would lead to a large difference inthe amount of active per film. If such films were to include low dosagesof active, it is possible that portions of the film may be substantiallydevoid of any active. Since sheets of film are usually cut into unitdoses, certain doses may therefore be devoid of or contain aninsufficient amount of active for the recommended treatment. Failure toachieve a high degree of accuracy with respect to the amount of activeingredient in the cut film can be harmful to the patient. For thisreason, dosage forms formed by processes such as Fuchs, would not likelymeet the stringent standards of governmental or regulatory agencies,such as the U.S. Federal Drug Administration (“FDA”), relating to thevariation of active in dosage forms. Currently, as required by variousworld regulatory authorities, dosage forms may not vary more than 10% inthe amount of active present. When applied to dosage units based onfilms, this virtually mandates that uniformity in the film be present.

The problems of self-aggregation leading to non-uniformity of a filmwere addressed in U.S. Pat. No. 4,849,246 to Schmidt (“Schmidt”).Schmidt specifically pointed out that the methods disclosed by Fuchs didnot provide a uniform film and recognized that that the creation of anon-uniform film necessarily prevents accurate dosing, which asdiscussed above is especially important in the pharmaceutical area.Schmidt abandoned the idea that a mono-layer film, such as described byFuchs, may provide an accurate dosage form and instead attempted tosolve this problem by forming a multi-layered film. Moreover, hisprocess is a multi-step process that adds expense and complexity and isnot practical for commercial use.

Other U.S. Patents directly addressed the problems of particleself-aggregation and non-uniformity inherent in conventional filmforming techniques. In one attempt to overcome non-uniformity, U.S. Pat.No. 5,629,003 to Horstmann et al. and U.S. Pat. No. 5,948,430 to Zerbeet al. incorporated additional ingredients, i.e. gel formers andpolyhydric alcohols respectively, to increase the viscosity of the filmprior to drying in an effort to reduce aggregation of the components inthe film. These methods have the disadvantage of requiring additionalcomponents, which translates to additional cost and manufacturing steps.Furthermore, both methods employ the use the conventional time-consumingdrying methods such as a high-temperature air-bath using a drying oven,drying tunnel, vacuum drier, or other such drying equipment. The longlength of drying time aids in promoting the aggregation of the activeand other adjuvant, notwithstanding the use of viscosity modifiers. Suchprocesses also run the risk of exposing the active, i.e., a drug, orvitamin C, or other components to prolonged exposure to moisture andelevated temperatures, which may render it ineffective or even harmful.

In addition to the concerns associated with degradation of an activeduring extended exposure to moisture, the conventional drying methodsthemselves are unable to provide uniform films. The length of heatexposure during conventional processing, often referred to as the “heathistory”, and the manner in which such heat is applied, have a directeffect on the formation and morphology of the resultant film product.Uniformity is particularly difficult to achieve via conventional dryingmethods where a relatively thicker film, which is well-suited for theincorporation of a drug active, is desired. Thicker uniform films aremore difficult to achieve because the surfaces of the film and the innerportions of the film do not experience the same external conditionssimultaneously during drying. Thus, observation of relatively thickfilms made from such conventional processing shows a non-uniformstructure caused by convection and intermolecular forces and requiresgreater than 10% moisture to remain flexible. The amount of freemoisture can often interfere over time with the drug leading to potencyissues and therefore inconsistency in the final product.

Conventional drying methods generally include the use of forced hot airusing a drying oven, drying tunnel, and the like. The difficulty inachieving a uniform film is directly related to the rheologicalproperties and the process of water evaporation in the film-formingcomposition. When the surface of an aqueous polymer solution iscontacted with a high temperature air current, such as a film-formingcomposition passing through a hot air oven, the surface water isimmediately evaporated forming a polymer film or skin on the surface.This seals the remainder of the aqueous film-forming composition beneaththe surface, forming a barrier through which the remaining water mustforce itself as if is evaporated in order to achieve a dried film. Asthe temperature outside the film continues to increase, water vaporpressure builds up under the surface of the film, stretching the surfaceof the film, and ultimately ripping the film surface open allowing thewater vapor to escape. As soon as the water vapor has escaped, thepolymer film surface reforms, and this process is repeated, until thefilm is completely dried. The result of the repealed destruction andreformation of the film surface is observed as a “ripple effect” whichproduces an uneven, and therefore non-uniform film. Frequently,depending on the polymer, a surface will seal so tightly that theremaining water is difficult to remove, leading to very long dryingtimes, higher temperatures, and higher energy costs.

Other factors, such as mixing techniques, also play a role in themanufacture of a pharmaceutical film suitable for commercialization andregulatory approval. Air can be trapped in the composition during themixing process or later during the film making process, which can leavevoids in the film product as the moisture evaporates during the dryingstage. The film frequently collapse around the voids resulting in anuneven film surface and therefore, non-uniformity of the final filmproduct. Uniformity is still affected even if the voids in the filmcaused by air bubbles do not collapse. This situation also provides anon-uniform film in that the spaces, which are not uniformlydistributed, are occupying area that would otherwise be occupied by thefilm composition. None of the above-mentioned patents either addressesor proposes a solution to the problems caused by air that has beenintroduced to the film.

Another goal in the manufacture of films to be used as a delivery systemis the minimization of materials or components. Because the films areoften very thin, it can be a challenge to incorporate a high load ofactive ingredient while maintaining the film's uniformity.

Another factor affecting the uniformity of films is the prevention ofair bubbles in the film. Anti-foaming and/or defoaming components may beused to aid in the removal of air, such as entrapped air, from thefilm-forming compositions. Such entrapped air may lead to non-uniformfilms.

Anti-foaming/defoaming components typically have a lowhydrophilic/lipophilic balance. In other words, they are often oily. Oneexample of a conventional anti-foaming/defoaming component issimethicone. Simethicone is a mixture of fully methylated linearsiloxane polymers containing repeating units of polydimethylsiloxanewhich is stabilized with trimethylsiloxy end-blocking unites, andsilicon dioxide, it usually contains 90.5-99% polymethylsiloxane and4-7% silicon dioxide. The mixture is a gray, translucent, viscous fluidwhich is insoluble in water. When dispersed in water, simethicone willspread across the surface, forming a thin film of low surface tension.In this way, simethicone reduces the surface tension of bubbles airlocated in the solution, such as foam bubbles, causing their collapse.The function of simethicone mimics the dual action of oil and alcohol inwater. For example, in an oily solution any trapped air bubbles willascend to the surface and dissipate more quickly and easily, because anoily liquid has a lighter density compared to a water solution. On theother hand, an alcohol/water mixture is known to lower water density aswell as lower the water's surface tension. So, any air bubbles trappedinside this mixture solution will also be dissipated. Simethicone actsas a anti-foaming/defoaming component by both lowering the surfaceenergy of any air bubbles trapped inside the aqueous solution, as wellas lowering the surface tension of the aqueous solution.

However, the anti-foaming/defoaming components themselves can sometimesalso lead to non-uniform films. Because of the nature ofanti-foaming/defoaming components, they can cause mottling of theproduct, i.e., clear spots in the translucent film.

Therefore, there is a need for methods and compositions for filmproducts, which use a minimal number of materials or components, andwhich provide a substantially non-self-aggregating uniform heterogeneitythroughout the area of the film.

SUMMARY OF THE INVENTION

In accordance with the present invention, an edible water-soluble filmis provided. The edible water-soluble film includes at least onewater-soluble polymer, and a foam reducing flavoring agent, wherein thefilm is free of added anti-foaming or defoaming agents.

In a preferred embodiment, the foam reducing flavoring agent is presentin amount of about 0.1% to about 20% by weight of the film. In anotherpreferred embodiment, the foam reducing flavoring agent is present inamount of about 0.5% to about 15% by weight of the film.

In a preferred embodiment, the foam reducing flavoring agent is fruit oraromatic or bark based. In another preferred embodiment, the foamreducing flavoring agent is selected from the group consisting ofmenthol cherry menthol, cinnamint, spearmint, peppermint, orange flavor,natural raspberry and combinations thereof. In another preferredembodiment, the foam reducing flavoring agent includes 8 to 12 carbonatoms, at least one terminal dimethyl group, and a non-terminal OHgroup.

In another preferred embodiment, the water-soluble polymer includes apolymer selected from the group consisting of a cellulosic material,polyethylene oxide, a polysaccharide, a gum, a protein, a starch, aglucan, and combinations thereof. In another embodiment, thewater-soluble polymer is selected from the group consisting ofcarboxymethyl cellulose, hydroxyl methyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose hydroxypropylmethyl cellulose,polyethylene oxide, and combinations thereof. In another embodiment, thewater-soluble polymer is selected from the group consisting of gumarabic, xanthan gum, tragacanth, acacia, carageenan, guar gum, locustbean gum, pectin, alginates and combinations thereof. In anotherembodiment, the water-soluble polymer is selected from the groupconsisting of polydextrose, dextrin, dextran and combinations thereof.

The film can also include an active component. In one embodiment, theactive component is selected from the group consisting of cosmeticagents, pharmaceutical agents, bioactive agents and combinationsthereof. In another embodiment, the active component is present inamounts of up to about 60% by weight of the film.

The film can further include one or more agents selected from the groupconsisting of taste-masking agents, plasticizing agents, surfactants,emulsifying agents, thickening agents, binding agents, cooling agents,saliva-stimulating agents, sweetening agents, antimicrobial agents andcombinations thereof.

In another aspect of the invention, a method of preparing asubstantially uniform film composition is provided. The method includes:

-   -   a) preparing a film-forming composition comprising a        water-soluble polymer, a foam reducing flavoring agent, and a        polar solvent;    -   b) mixing said film-forming composition under vacuum;    -   c) casting said film-forming composition; and    -   d) removing said polar solvent through a controlled drying        process.

The edible water-soluble film of the invention provides a substantiallynon-self-aggregating uniform heterogeneity throughout the area of thefilm. By utilizing a foam reducing flavoring agent, instead of aconventional foam reducing agent, the film of the present invention hasa uniform appearance, without mottling. Also, by avoiding the additionof a conventional foam reducing agent, the film of the present inventioncan accommodate added active ingredient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a side view of a package containing a unit dosage film ofthe present invention.

FIG. 2 shows a top view of two adjacently coupled packages containingindividual unit dosage forms of the present invention, separated by atearable perforation.

FIG. 3 shows a side view of the adjacently coupled packages of FIG. 2arranged in a stacked configuration.

FIG. 4 shows a perspective view of a dispenser for dispensing thepackaged unit dosage forms, dispenser containing the packaged unitdosage forms in a stacked configuration.

FIG. 5 is a schematic view of a roll of coupled unit dose packages ofthe present invention.

FIG. 6 is a schematic view of an apparatus suitable for preparation of apre-mix, addition of an active, and subsequent formation of the film.

FIG. 7 is a schematic view of an apparatus suitable for drying the filmsof the present invention.

FIG. 8 is a sequential representation of the drying process of thepresent invention.

FIG. 9 is a schematic representation of a continuously-linked zonedrying apparatus in accordance with the present invention.

FIG. 10 is a schematic representation of a separate zone dryingapparatus in accordance with the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an edible water-soluble film. The filmincludes at least one soluble polymer. In addition, unlike conventionalfilms, the film of the invention is free of added anti-foaming ordefoaming agents. Instead, the present invention utilizes a foamreducing flavoring agent to provide a non-self-aggregating uniform film.

For the purposes of the present invention the term non-self-aggregatinguniform heterogeneity refers to the ability of the films of the presentinvention, which are formed from one or more components in addition to apolar solvent, to provide a substantially reduced occurrence of, i.e.little or no, aggregation or conglomeration of components within thefilm as is normally experienced when films are formed by conventionaldrying methods such as a high-temperature air-bath using a drying oven,drying tunnel, vacuum drier, or other such drying equipment. The termheterogeneity, as used in the present invention, includes films thatwill incorporate a single component, such as a polymer, as well ascombinations of components, such as a polymer and an active. Uniformheterogeneity includes the substantial absence of aggregates orconglomerates as is common in conventional mixing and heat dryingmethods used to form films.

Furthermore, the films of the present invention have a substantiallyuniform thickness, which is also not provided by the use of conventionaldrying methods used for drying water-based polymer systems. The absenceof a uniform thickness detrimentally affects uniformity of componentdistribution throughout the area of a given film.

The film products of the present invention are produced by a combinationof a properly selected polymer and a polar solvent, optionally includingan active ingredient as well as other fillers known in the art. Thesefilms provide a non-self-aggregating uniform heterogeneity of thecomponents within them by utilizing a selected casting or depositionmethod and a controlled drying process. Examples of controlled dryingprocesses include, but are not limited to, the use of the apparatusdisclosed in U.S. Pat. No. 4,631,837 to Magoon (“Magoon”), hereinincorporated by reference, as well as hot air impingement across thebottom substrate and bottom heating plates. Another drying technique forobtaining the films of the present invention is controlled radiationdrying, in the absence of uncontrolled air currents, such as infraredand radio frequency radiation (i.e. microwaves).

The objective of the drying process is to provide a method of drying thefilms that avoids complications, such as the noted “rippling” effect,that are associated with conventional drying methods and which initiallydry the upper surface of the film, trapping moisture inside. Inconventional oven drying methods, as the moisture trapped insidesubsequently evaporates, the top surface is altered by being ripped openand then reformed.

These complications are avoided by the present invention, and a uniformfilm is provided by drying the bottom surface of the film first orotherwise preventing the formation of polymer film formation (skin) onthe top surface of the film prior to drying the depth of the film. Thismay be achieved by applying heat to the bottom surface of the film withsubstantially no top air flow, or alternatively by the introduction ofcontrolled microwaves to evaporate the water or other polar solventwithin the film, again with substantially no top air flow.

Yet alternatively, drying may be achieved by using balanced fluid flow,such as balanced air flow, where the bottom and top air flows arecontrolled to provide a uniform film. In such a case, the air flowdirected at the top of the film should not create a condition whichwould cause movement of particles present in the wet film, due to forcesgenerated by the air currents.

Additionally, air currents directed at the bottom of the film shoulddesirably be controlled such that the film does not lift up due toforces from the air. Uncontrolled air currents, either above or belowthe film, can create non-uniformity in the final film products. Thehumidity level of the area surrounding the top surface may also beappropriately adjusted to prevent premature closure or skinning of thepolymer surface.

This manner of drying the films provides several advantages. Among theseare the faster drying times and a more uniform surface of the film, aswell as uniform distribution of components for any given area in thefilm. In addition, the faster drying time allows viscosity to quicklybuild within the film, further encouraging a uniform distribution ofcomponents and decrease in aggregation of components in the final filmproduct. Desirably, the drying of the film will occur within about tenminutes or fewer, or more desirably within about five minutes or fewer.

The present invention yields exceptionally uniform film products whenattention is paid to reducing the aggregation of the compositionalcomponents. By avoiding the introduction of and eliminating excessiveair in the mixing process, selecting polymers and solvents to provide acontrollable viscosity and by drying the film in a rapid manner from thebottom up, such films result.

The products and processes of the present invention rely on theinteraction among various steps of the production of the films in orderto provide films that substantially reduce the self-aggregation of thecomponents within the films. Specifically, these steps include theparticular method used to form the film, making the composition mixtureto prevent air bubble inclusions, controlling the viscosity of the filmforming composition and the method of drying the film. Moreparticularly, a greater viscosity of components in the mixture isparticularly useful when the active is not soluble in the selected polarsolvent in order to prevent the active from settling out. However, theviscosity must not be too great as to hinder or prevent the chosenmethod of casting, which desirably includes reverse roll coating due toits ability to provide a film of substantially consistent thickness.

In addition to the viscosity of the film or film-forming components ormatrix, there are other considerations taken into account by the presentinvention for achieving desirable film uniformity. For example, stablesuspensions are achieved which prevent solid (such as drug particles)sedimentation in non-colloidal applications. One approach provided bythe present invention is to balance the density of the particulate(ρ_(p)) and the liquid phase (ρ₁) and increase the viscosity of theliquid phase (μ). For an isolated particle, Stokes law relates theterminal settling velocity (Vo) of a rigid spherical body of radius (r)in a viscous fluid, as follows:V _(o)=(2gr ^(F))(ρ_(p)−ρ₁)/9μ

At high particle concentrations, however, the local particleconcentration will affect the local viscosity and density. The viscosityof the suspension is a strong function of solids volume fraction, andparticle-particle and particle-liquid interactions will further hindersettling velocity.

Stokian analyses has shown that the incorporation of a third phase,dispersed air or nitrogen, for example, promotes suspension stability.Further, increasing the number of particles leads to a hindered settlingeffect based on the solids volume fraction. In dilute particlesuspensions, the rate of sedimentation, v, can be expressed as:v/V _(o)=1/(1+κφ)

where κ=a constant and φ is the volume fraction of the dispersed phase.More particles suspended in the liquid phase results in decreasedvelocity. Particle geometry is also an important factor since theparticle dimensions will affect particle-particle flow interactions.

Similarly, the viscosity of the suspension is dependent on the volumefraction of dispersed solids. For dilute suspensions of non-interactionspherical particles, an expression for the suspension viscosity can beexpressed as:μ/μ_(o)=1+2.5φ

where μ_(o) is the viscosity of the continuous phase and φ is the solidsvolume fraction. At higher volume fractions, the viscosity of thedispersion can be expressed asμ/μ_(o)=1+2.5φ+C ₁φ² +C ₂φ³+

where C is a constant.

The viscosity of the liquid phase is critical and is desirably modifiedby customizing the liquid composition to a viscoelastic non-Newtonianfluid with low yield stress values. This is the equivalent of producinga high viscosity continuous phase at rest. Formation of a viscoelasticor a highly structured fluid phase provides additional resistive forcesto particle sedimentation. Further, flocculation or aggregation can becontrolled minimizing particle-particle interactions. The net effectwould be the preservation of a homogeneous dispersed phase.

The addition of hydrocolloids to the aqueous phase of the suspensionincreases viscosity, may produce viscoelasticity and can impartstability depending on the type of hydrocolloid, its concentration andthe particle composition, geometry, size, and volume fraction. Theparticle size distribution of the dispersed phase needs to be controlledby selecting the smallest realistic particle size in the high viscositymedium, i.e., <500 μm. The presence of a slight yield stress or elasticbody at low shear rates may also induce permanent stability regardlessof the apparent viscosity. The critical particle diameter can becalculated from the yield stress values. In the case of isolatedspherical particles, the maximum shear stress developed in settlingthrough a medium of given viscosity can be given asτ_(max)=3Vμ/2rFor pseudoplastic fluids, the viscosity in tins shear stress regime maywell be the zero shear rate viscosity at the Newtonian plateau.

A stable suspension is an important characteristic for the manufactureof a pre-mix composition which is to be fed into the film castingmachinery film, as well as the maintenance of this stability in the wetfilm stage until sufficient drying has occurred to lock-in the particlesand matrix into a sufficiently solid form such that uniformity ismaintained. For viscoelastic fluid systems, a rheology that yieldsstable suspensions for extended time period, such as 24 hours, must bebalanced with the requirements of high-speed film casting operations. Adesirable property for the films is shear thinning or pseudoplasticity,whereby the viscosity decreases with increasing shear rate. Timedependent shear effects such as thixotropy are also advantageous.Structural recovery and shear thinning behavior are importantproperties, as is the ability for the film to self-level as it isformed.

The rheology requirements for the inventive compositions and films arequite severe. This is due to the need to produce a stable suspension ofparticles, for example 30-60 wt. %, in a viscoelastic fluid matrix withacceptable viscosity values throughout a broad shear rate range. Duringmixing, pumping, and film casting, shear rates in the range of 10-10⁵sec.⁻¹ may be experienced and pseudoplasticity is the preferredembodiment.

In film casting or coating, rheology is also a defining factor withrespect to the ability to form films with the desired uniformity. Shearviscosity, extensional viscosity, viscoelasticity, structural recoverywill influence the quality of the film. As an illustrative example, theleveling of shear-thinning pseudoplastic fluids has been derived asα^((n−1/n))=α_(o) ^((n−1/n))−((n−1)/(2n−1))(τ/K)^(1/n)(2π/λ)^((3+n)/n) h^((2n+1)/n) t

where α is the surface wave amplitude, α_(o) is the initial amplitude, λis the wavelength of the surface roughness, and both “n” and “K” areviscosity power law indices. In this example, leveling behavior isrelated to viscosity, increasing as n decreases, and decreasing withincreasing K.

Desirably, the films or film-forming compositions of the presentinvention have a very rapid structural recovery, i.e. as the film isformed during processing, it doesn't fall apart or become discontinuousin its structure and compositional uniformity. Such very rapidstructural recovery retards particle settling and sedimentation.Moreover, the films or film-forming compositions of the presentinvention are desirably shear-thinning pseudoplastic fluids. Such fluidswith consideration of properties, such as viscosity and elasticity,promote thin film formation and uniformity.

Thus, uniformity in the mixture of components depends upon numerousvariables. As described herein, viscosity of the components, the mixingtechniques and the rheological properties of the resultant mixedcomposition and wet casted film are important aspects of the presentinvention. Additionally, control of particle size and particle shape arefurther considerations. Desirably, the size of the particulate aparticle size of 150 microns or less, for example 100 microns or less.Moreover, such particles may be spherical, substantially spherical, ornon-spherical, such as irregularly shaped particles or ellipsoidallyshaped particles. Ellipsoidally shaped particles or ellipsoids aredesirable because of their ability to maintain uniformity in the filmforming matrix as they tend to settle to a lesser degree as compared tospherical particles.

In addition to adding a foam reducing flavoring agent, as furtherdiscussed below, a number of techniques may be employed in the mixingstage to prevent bubble inclusions in the final film. To provide acomposition mixture with substantially no air bubble formation in thefinal product, the speed of the mixture is desirably controlled toprevent cavitation of the mixture in a manner which pulls air into themix. Finally, air bubble reduction can further be achieved by allowingthe mix to stand for a sufficient time for bubbles to escape prior todrying the film. Desirably, the inventive process first forms amasterbatch of film-forming components without active ingredients suchas drug particles. The actives are added to smaller mixes of themasterbatch just prior to casting. Thus, the masterbatch pre-mix can beallowed to stand for a longer time without concern for instability indrug or other ingredients.

When the matrix is formed including the film-forming polymer and polarsolvent in addition to any additives and the active ingredient, this maybe done in a number of steps. For example, the ingredients may all beadded together or a pre-mix may be prepared. The advantage of a pre-mixis that all ingredients except for the active may be combined inadvance, with the active added just prior to formation of the film. Thisis especially important for actives that may degrade with prolongedexposure to water, air or another polar solvent.

FIG. 6 shows an apparatus 20 suitable for the preparation of a pre-mix,addition of an active and subsequent formation of a film. The pre-mix ormaster batch 22, which includes the film-forming polymer, polar solvent,and any other additives except a drug active is added to the masterbatch feed tank 24. The components for pre-mix or master batch 22 aredesirably formed in a mixer (not shown) prior to their addition into themaster batch feed tank 24. Then a pre-determined amount of the masterbatch is controllably fed via a first metering pump 26 and control valve28 to either or both of the first and second mixers, 30, 30′. Thepresent invention, however, is not limited to the use of two mixers, 30,30′, and any number of mixers may suitably be used. Moreover, thepresent invention is not limited to any particular sequencing of themixers 30, 30′, such as parallel sequencing as depicted in FIG. 6, andother sequencing or arrangements of mixers, such as series orcombination, of parallel and series, may suitably be used. The requiredamount of the drug or other ingredient, such as a flavor, is added tothe desired mixer through an opening, 32, 32′, in each of the mixers,30, 30′. Desirably, the residence time of the pre-mix or master batch 22is minimized in the mixers 30, 30′. While complete dispersion of thedrug into the pre-mix or master batch 22 is desirable, excessiveresidence times may result in leaching or dissolving of the drug,especially in the case for a soluble drug. Thus, the mixers 30, 30′ areoften smaller, i.e. lower residence times, as compared to the primarymixers (not shown) used in forming the pre-mix or master batch 22. Afterthe drug has been blended with the master batch pre-mix for a sufficienttime to provide a uniform matrix, a specific amount of the uniformmatrix is then fed to the pan 36 through tire second metering pumps, 34,34′. The metering roller 38 determines the thickness of the film 42 andapplies it to the application roller. The film 42 is finally formed onthe substrate 44 and carried away via the support roller 46.

While the proper viscosity uniformity in mixture and stable suspensionof particles, and casting method are important in the initial steps offorming the composition and film to promote uniformity, the method ofdrying the wet film is also important. Although these parameters andproperties assist uniformity initially, a controlled rapid dryingprocess ensures that the uniformity will be maintained until the film isdry.

The wet film is then dried using controlled bottom drying or controlledmicrowave drying, desirably in the absence of external air currents orheat on the top (exposed) surface of the film 48 as described herein.Controlled bottom drying or controlled microwave drying advantageouslyallows for vapor release from the film without the disadvantages of theprior art. Conventional convection air drying from the top is notemployed because it initiates drying at the top uppermost portion of thefilm, thereby forming a barrier against fluid flow, such as theevaporative vapors, and thermal flow, such as the thermal energy fordrying. Such dried upper portions serve as a barrier to further vaporrelease as the portions beneath are dried, which results in non-uniformfilms. As previously mentioned some top air flow can be used to aid thedrying of the films of the present invention, but it must not create acondition that would cause particle movement or a rippling effect in thefilm, both of which would result in non-uniformity. If top air isemployed, it is balanced with the bottom air drying to avoidnon-uniformity and prevent film lift-up on the carrier belt. A balancetop and bottom air flow may be suitable where the bottom air flowfunctions as the major source of drying and the top air How is the minorsource of drying. The advantage of some top air flow is to move theexiting vapors away from the film thereby aiding in the overall dryingprocess. The use of any top air flow or top drying, however, must bebalanced by a number of factors including, but not limited, torheological properties of the composition and mechanical aspects of theprocessing. Any top fluid flow, such as air, also must not overcome theinherent viscosity of the film-forming composition. In other words, thetop air flow cannot break, distort or otherwise physically disturb thesurface of the composition. Moreover, air velocities are desirably belowthe yield values of the film, i.e., below any force level that can movethe liquids in the film-forming compositions. For thin or low viscositycompositions, low air velocity must be used. For thick or high viscositycompositions, higher air velocities may be used. Furthermore, airvelocities are desirable low so as to avoid any lifting or othermovement of the film formed from the compositions.

Moreover, the films of the present invention may contain particles thatare sensitive to temperature, such as flavors, which may be volatile, ordrugs, which may have a low degradation temperature. In such cases, thedrying temperature may be decreased while increasing the drying time toadequately dry the uniform films of the present invention. Furthermore,bottom drying also tends to result in a lower internal film temperatureas compared to top drying. In bottom drying, the evaporating vapors morereadily carry heat away from the film as compared to top drying whichlowers the internal film temperature. Such lower internal filmtemperatures often result in decreased drug degradation and decreasedloss of certain volatiles, such as flavors.

During film preparation, it may be desirable to dry films at hightemperatures. High heat drying produces uniform films, and leads togreater efficiencies in film production. Films containing sensitiveactive components, however, may face degradation problems at hightemperatures. Degradation is the “decomposition of a compound . . .exhibiting well-defined intermediate products.” The American HeritageDictionary of the English Language (4^(th) ed. 2000). Degradation of anactive component is typically undesirable as it may cause instability,inactivity, and/or decreased potency of the active component. Forinstance, if the active component is a drug or bioactive material, thismay adversely affect the safety or efficacy of the final pharmaceuticalproduct. Additionally, highly volatile materials will tend to be quicklyreleased from this film upon exposure to conventional drying methods.

Degradation of an active component may occur through a variety ofprocesses, such as, hydrolysis, oxidation, and light degradation,depending upon the particular active component. Moreover, temperaturehas a significant effect on the rate of such reactions. The rate ofdegradation typically doubles for every 10° C. increase in temperature.Therefore, it is commonly understood that exposing an active componentto high temperatures will initiate and/or accelerate undesirabledegradation reactions.

Proteins are one category of useful active agents that may degrade,denature, or otherwise become inactive when they are exposed to hightemperatures for extended periods of time. Proteins serve a variety offunctions in the body such as enzymes, structural elements, hormones andimmunoglobulins. Examples of proteins include enzymes such aspancreatin, trypsin, pancrelipase, chymotrypsin, hyaluronidase,sutilains, streptokinaw, urokinase, altiplase, papain,bromelainsdiastase, structural elements such as collagen, elastin andalbumin, hormones such as thyroliberin, gonadoliberin,adrenocorticottropin, corticotrophin, cosyntropin, sometrem,somatropion, prolactin, thyrotropin, somatostatin, vasopressin,felypressin, lypressin, insulin, glucagons, gastrin, pentagastrin,secretin, cholecystokinin-pancreozymin, and immunomodulatory which mayinclude polysaccharides in addition to glycoproteins including cytokineswhich are useful for the inhibition and prevention of malignant cellgrowth such as tumor growth. A suitable method for the production ofsome useful glycoproteins is disclosed in U.S. Pat. No. 6,281,337 toCannon-Carlson, et al., which in incorporated herein in its entirety.

Peptides are another category of useful active agents that have thepotential to become inactive when exposed to high temperatures for longperiods of time.

Temperatures that approach 100° C. will generally cause degradation ofproteins, certain peptides, as well as nucleic acids. For example, someglycoproteins will degrade if exposed to a temperature of 70° C. forthirty minutes. Proteins from bovine extract are also known to degradeat such low temperatures. DNA also begins to denature at thistemperature.

Applicants have discovered, however, that the films of the presentinvention may be exposed to high temperatures during the drying processwithout concern for degradation, loss of activity, or excessiveevaporation due to the inventive process for film preparation andforming. In particular, the films may be exposed to temperatures thatwould typically lead to degradation, denaturization, or inactivity ofthe active component, without causing such problems. According to thepresent invention, the manner of drying may be controlled to preventdeleterious levels of heat from reaching the active component.

As discussed herein, the flowable mixture is prepared to be uniform incontent in accordance with the teachings of the present invention.Uniformity must be maintained as the flowable mass was formed into afilm and dried. During the drying process of the present invention,several factors produce uniformity within the film while maintaining theactive component at a safe temperature, i.e., below its degradationtemperature. First, the films of the present invention have an extremelyshort heat history, usually only on the order of minutes, so that totaltemperature exposure is minimized to the extent possible. The films arecontrollably dried to prevent aggregation and migration of components,as well as preventing heat build up within. Desirably, the films aredried from the bottom. Controlled bottom drying, as described herein,prevents the formation of a polymer film, or skin, on the top surface ofthe film. As heat is conducted from the film bottom upward, liquidcarrier, e.g., water, rises to the film surface. The absence of asurface skin permits rapid evaporation of the liquid carrier as thetemperature increases, and thus, concurrent evaporative cooling of thefilm. Due to the short heat exposure and evaporative cooling, the filmcomponents such as drag or volatile actives remain unaffected by hightemperatures. In contrast, skinning on the top surface traps liquidcarrier molecules of increased energy within the film, thereby causingthe temperature within the film to rise and exposing active componentsto high, potentially deleterious temperatures.

Second, thermal mixing occurs within the film due to bottom heating andabsence of surface skinning. Thermal mixing occurs via convectioncurrents in the film. As heat is applied to the bottom of the film, theliquid near the bottom increases in temperature, expands, and becomesless dense. As such, this hotter liquid rises and cooler liquid takesits place. While rising, the hotter liquid mixes with the cooler liquidand shares thermal energy with it, i.e., transfers heat. As the cyclerepeats, thermal energy is spread throughout the film.

Robust thermal mixing achieved by the controlled drying process of thepresent invention produces uniform heat diffusion throughout the film.In the absence of such thermal mixing, “hot spots” may develop. Pocketsof heat in the film result in the formation of particle aggregates ordanger areas within the film and subsequent non-uniformity. Theformation of such aggregates or agglomerations is undesirable because itleads to non-uniform films in which the active may be randomlydistributed. Such uneven distribution may lead to large differences inthe amount of active per film, which is problematic from a safety andefficacy perspective.

Furthermore, thermal mixing helps to maintain a lower overalltemperature inside the film. Although the film surfaces may be exposedto a temperature above that at which the active component degrades, thefilm interior may not reach this temperature. Due to this temperaturedifferential, the active does not degrade.

For instance, the films of the present invention desirably are dried for10 minutes or less. Drying the films at 80° C. for 10 minutes produces atemperature differential of about 5° C. This means that after 10 minutesof drying, the temperature of the inside of the film is 5° C. less thanthe outside exposure temperature. In many cases, however, drying timesof less than 10 minutes are sufficient, such as 4 to 6 minutes. Dryingfor 4 minutes may be accompanied by a temperature differential of about30° C., and drying for 6 minutes may be accompanied by a differential ofabout 25° C. Due to such large temperature differentials, the films maybe dried at efficient, high temperatures without causing heat sensitiveactives to degrade.

FIG. 8 is a sequential representation of the drying process of thepresent invention. After mechanical mixing, the film may be placed on aconveyor for continued thermal mixing during the drying process. At theoutset of the drying process, depicted in Section A, the film 1preferably is heated from the bottom 10 as it is travels via conveyor(not shown). Heat may be supplied to the film by a heating mechanism,such as, but not limited to, the dryer depicted in FIG. 7. As the filmis heated, the liquid carrier, or volatile (“V”), begins to evaporate,as shown by upward arrow 50. Thermal mixing also initiates as hotterliquid, depicted by arrow 30, rises and cooler liquid, depicted by arrow40, takes its place. Because no skin forms on the top surface 20 of thefilm 1, as shown in Section B the volatile liquid continues to evaporate50 and thermal mixing 30/40 continues to distribute thermal energythroughout the film. Once a sufficient amount of the volatile liquid hasevaporated, thermal mixing has produced uniform heat diffusionthroughout the film 1. The resulting dried film 1 is a visco-elasticsolid, as depicted in Section C. The components desirably are lockedinto a uniform distribution throughout the film. Although minor amountsof liquid carrier, i.e., water, may remain subsequent to formation ofthe visco-elastic, the film may be dried further without movement of theparticles, if desired.

Furthermore, particles or particulates may be added to the film-formingcomposition or matrix after the composition or matrix is cast into afilm. For example, particles may be added to the film 42 prior to thedrying of the film 42. Particles may be controllably metered to the filmand disposed onto the film through a suitable technique, such as throughthe use of a doctor blade (not shown) which is a device which marginallyor softly touches the surface of the film and controllably disposes theparticles onto the film surface. Other suitable, but non-limiting,techniques include the use of an additional roller to place theparticles on the film surface, spraying the particles onto the filmsurface, and the like. The particles may be placed on either or both ofthe opposed film surfaces, i.e., the top and/or bottom film surfaces.Desirably, the particles are securably disposed onto the film, such asbeing embedded into the film. Moreover, such particles are desirably notfully encased or fully embedded into the film, but remain exposed to thesurface of the film, such as in the case where the particles arepartially embedded or partially encased.

The particles may be any useful organoleptic agent, cosmetic agent,pharmaceutical agent, or combinations thereof. Desirably, thepharmaceutical agent is a taste-masked or a controlled-releasepharmaceutical agent. Useful organoleptic agents include flavors andsweeteners. Useful cosmetic agents include breath freshening ordecongestant agents.

Although the inventive process is not limited to any particularapparatus for the above-described desirable drying, one particularuseful drying apparatus 50 is depicted in FIG. 7. Drying apparatus 50 isa nozzle arrangement for directing hot fluid, such as but not limited tohot air, towards the bottom of the film 42 which is disposed onsubstrate 44. Hot air enters the entrance end 52 of the drying apparatusand travels vertically upward, as depicted by vectors 54, towards airdeflector 56. The air deflector 56 redirects the air movement tominimize upward force on the film 42. As depicted in FIG. 7, the air istangentially directed, as indicated by vectors 60 and 60′, as the airpasses by air deflector 56 and enters and travels through chamberportions 58 and 58′ of the drying apparatus 50. With the hot air flowbeing substantially tangential to the film 42, lifting of the film as itis being dried is thereby minimized. While the air deflector 56 isdepicted as a roller, other devices and geometries for deflecting air orhot fluid may suitable be used. Furthermore, the exit ends 62 and 62′ ofthe drying apparatus 50 are flared downwardly. Such downward flaringprovides a downward force or downward velocity vector, as indicated byvectors 64 and 64′, which tend to provide a pulling or drag effect ofthe film 42 to prevent lifting of the film 42. Lifting of the film 42may not only result in non-uniformity in the film or otherwise, but mayalso result in non-controlled processing of the film 42 as the film 42and/or substrate 44 lift away from the processing equipment.

Monitoring and control of the thickness of the film also contributes tothe production of a uniform film by providing a film of uniformthickness. The thickness of the film may be monitored with gauges suchas Beta Gauges. A gauge may be coupled to another gauge at the end ofthe drying apparatus, i.e. drying oven or tunnel, to communicate throughfeedback loops to control and adjust the opening in the coatingapparatus, resulting in control of uniform film thickness.

The film products are generally formed by combining a properly selectedpolymer and polar solvent, as well as any active ingredient or filler asdesired. Desirably, the solvent content of the combination is at leastabout 30% by weight of the total combination. The matrix formed by thiscombination is formed into a film, desirably by roll coating, and thendried, desirably by a rapid and controlled drying process to maintaintire uniformity of the film, more specifically, a non-self-aggregatinguniform heterogeneity. The resulting film will desirably contain lessthan about 10% by weight solvent, more desirably less than about 8% byweight solvent, even more desirably less than about 6% by weight solventand most desirably less than about 2%. The solvent may be water, a polarorganic solvent including, but not limited to, ethanol, isopropanol,acetone, methylene chloride, or any combination thereof.

Consideration of the above discussed parameters, such as but not limitedto rheology properties, viscosity, mixing method, casting method anddrying method, also impact material selection for the differentcomponents of the present invention. Furthermore, such considerationwith proper material selection provides the compositions of the presentinvention, including a pharmaceutical and/or cosmetic dosage form orfilm product having no more than a 10% variance of a pharmaceuticaland/or cosmetic active per unit area. In other words, the uniformity ofthe present invention is determined by the presence of no more than a10% by weight of pharmaceutical and/or cosmetic variance throughout thematrix. Desirably, the variance is less than 5% by weight, less than 2%by weight, less than 1% by weight, or less than 0.5% by weight.

Fine-Forming Polymers

The film product of the present invention includes a water solublepolymer composition. The films include at least one water solublepolymer and may include other hydrophilic materials. The films may alsoinclude water swellable or water insoluble polymers, if desired.

In some embodiments, the water soluble polymer composition includes ahydrophilic material selected from the following: a saccharide-basedpolymer, a non-saccharide-based polymer, a sugar alcohol andcombinations thereof.

In some embodiments, the self-supporting film includes asaccharide-based polymer, which is water soluble. For example, thesaccharide-based polymer may be cellulose or a cellulose derivative.Specific examples of useful saccharide-based, water soluble polymersinclude, but are not limited to, polydextrose, pullulan,hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose (HPC),hydroxypropyl cellulose, carboxymethyl cellulose, sodium aginate,xanthan gum, tragancanth gum, guar gum, acacia gum, arabic gum, starch,gelatin, and combinations thereof.

In some preferred embodiments, the saccharide-based polymer may be atleast one cellulosic polymer, polydextrose, or combinations thereof.

The film may also include non-saccharide-based, water soluble or waterinsoluble polymers. Examples of non-saccharide based, water solublepolymers include polyethylene oxide, polyvinylpyrrolidone, polyvinylalcohol, polyethylene glycol, polyacrylic acid, methylmethacrylatecopolymer, carboxyvinyl copolymers, and combinations thereof.

In some embodiments, the water soluble polymer composition includes asugar alcohol. The sugar alcohol may be selected from, but is notlimited to, one of the following: erythritol, sorbitol and xylitol.

Specific examples of useful water insoluble polymers include, but arenot limited to, ethyl cellulose, hydroxypropyl ethyl cellulose,cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalateand combinations thereof. In some embodiments, the water soluble polymercomposition includes polyethylene oxide, alone or in combination withother hydrophilic materials.

In some embodiments, the water soluble polymer composition includes acombination of polyethylene oxide and polyvinylpyrrolidone. In otherembodiments, the water soluble polymer composition includes acombination of polyethylene oxide and polyvinyl alcohol.

In some other embodiments, the water soluble polymer compositionincludes polyethylene oxide in combination with a cellulosic polymer.For example, the water soluble polymer composition may include acombination of polyethylene oxide and carboxymethyl cellulose. Infurther embodiments, the water soluble polymer composition includes acombination of polyethylene oxide and hydroxypropyl cellulose. In stillfurther embodiments, the water soluble polymer composition includes acombination of polyethylene oxide and hydroxy propylmethyl cellulose.

In other embodiments, the water soluble polymer composition includespolyethylene oxide in combination with a sugar or sugar alcohol. Forexample, the water soluble polymer composition may include a combinationof polyethylene oxide and polydextrose. In other embodiments, the watersoluble polymer composition includes a combination of polyethylene oxideand erythritol. In further embodiments, the water soluble polymercomposition includes a combination of polyethylene oxide and sorbitol.In other embodiments, the water soluble polymer composition includes acombination of polyethylene oxide and xylitol.

In further embodiments, the water soluble polymer composition comprisesa combination of polyethylene oxide, hydroxypropyl methyl cellulose andpolydextrose.

As used herein, the phrase “water soluble polymer” and variants thereofrefer to a polymer that is at least partially soluble in a fluid, suchas water, and desirably fully or predominantly soluble in the fluid, orabsorbs the fluid. In some embodiments, the film product of the presentinvention is substantially dissolvable when exposed to a fluid.

Polymers that absorb water are often referred to as being waterswellable polymers. The materials useful with the present invention maybe water soluble or water swellable at room temperature and othertemperatures, such as temperatures exceeding room temperature. Moreover,the materials may be water soluble or water swellable at pressures lessthan atmospheric pressure. Desirably, the water soluble polymers arewater soluble or water swellable having at least 20 percent by weightwater uptake. Water swellable polymers having a 25 or greater percent byweight water uptake are also useful. Films or dosage forms of thepresent invention formed from such water soluble polymers are desirablysufficiently water soluble to be dissolvable upon contact with fluids.

Other polymers useful for incorporation into the films of the presentinvention include biodegradable polymers, copolymers, block polymers andcombinations thereof. Among the known useful polymers or polymer classeswhich meet the above criteria, are: poly(glycolic acid) (PGA),poly(lactic acid) (PLA), polydioxanoes, polyoxalates, poly(α-esters),polyanhydrides, polyacetates, polycaprolactones, poly(orthoesters),polyamino acids, polyaminocarbonates, polyurethanes, polycarbonates,polyamides, poly(alkyl cyanoacrylates), and mixtures and copolymersthereof. Additional useful polymers include, stereopolymers of L- andD-lactic acid, copolymers of bis(p-carboxyphenoxy)propane acid andsebacic acid, sebacic acid copolymers, copolymers of caprolactone,poly(lactic acid)/poly(glycolic acid)/polyethyleneglycol copolymers,copolymers of polyurethane and (poly(lactic acid), copolymers ofpolyurethane and poly(lactic acid), copolymers of α-amino acids,copolymers of α-amino acids and caproic acid, copolymers of α-benzylglutamate and polyethylene glycol, copolymers of succinate andpoly(glycols), polyphosphazene, polyhydroxy-alkanoates and mixturesthereof. Binary and ternary systems are contemplated.

Other specific polymers useful include those marketed under the Medisorband Biodel trademarks. The Medisorb materials are marketed by the DupontCompany of Wilmington, Del. and are generically identified as a“lactide/glycolide co-polymer” containing “propanoic acid,2-hydroxy-polymer with hydroxy-polymer with hydroxy acetic acid.” Foursuch polymers include lactide/glycolide 100 L, believed to be 100%lactide having a melting point within the range of 338°-347° F.(170°-175° C.); lactide/glycolide 100 L, believed to be 100% glycolidehaving a melting point within the range of 437°-455° F. (225°-235° C.);lactide/glycolide 85/15, believed to be 85% lactide and 15% glycolidewith a melting point within the range of 338°-347° F. (170°-175° C.);and lactide/glycolide 50/50, believed to be a copolymer of 50% lactideand 50% glycolide with a melting point within the range of 338°-347° F.(170°-175° C.).

The Biodel materials represent a family of various polyanhydrides whichdiffer chemically.

Although a variety of different polymers may be used, it is desired toselect polymers to provide a desired viscosity of the mixture prior todrying. For example, if the active agent or other components are notsoluble in the selected solvent, a polymer that will provide a greaterviscosity is desired to assist in maintaining uniformity. On the otherhand, if the components are soluble in the solvent, a polymer thatprovides a lower viscosity may be preferred.

The polymer plays an important role in affecting the viscosity of thefilm. Viscosity is one property of a liquid that controls the stabilityof the active agent in an emulsion, a colloid or a suspension. Generallythe viscosity of the matrix will vary from about 400 cps to about100,000 cps, preferably from about 800 cps to about 60,000 cps, and mostpreferably from about 1,000 cps to about 40,000 cps. Desirably, theviscosity of the film-forming matrix will rapidly increase uponinitiation of the drying process.

The viscosity may be adjusted based on the selected active agentcomponent, depending on the other components within the matrix. Forexample, if the component is not soluble within the selected solvent, aproper viscosity may be selected to prevent the component from settlingwhich would adversely affect the uniformity of the resulting film. Theviscosity may be adjusted in different ways. To increase viscosity ofthe film matrix, the polymer may be chosen of a higher molecular weightor crosslinkers may be added, such as salts of calcium, sodium andpotassium. The viscosity may also be adjusted by adjusting thetemperature or by adding a viscosity increasing component. Componentsthat will increase the viscosity or stabilize the emulsions/suspensioninclude higher molecular weight polymers and polysaccharides and gums,which include without limitation, alginate, carrageenan, hydroxypropylmethyl cellulose, locust bean gum, guar gum, xanthan gum, dextran, gumarabic, gellan gum and combinations thereof.

It has also been observed that certain polymers which when used alonewould ordinarily require a plasticizer to achieve a flexible film, canbe combined without a plasticizer and yet achieve flexible films. Forexample, HPMC and HPC when used in combination provide a flexible,strong film with the appropriate plasticity and elasticity formanufacturing and storage. No additional plasticizer or polyalcohol isneeded for flexibility.

Additionally, polyethylene oxide (PEO), when used alone or incombination with a hydrophilic cellulosic polymer and/or polydextroseachieves flexible, strong films. Additional plasticizers or polyalcoholsare not needed for flexibility. Non-limiting examples of suitablecellulosic polymers for combination with PEO include HPC and HPMC. PEOand HPC have essentially no gelation temperature, while HPMC has agelation temperature of 58-64° C. (Methocel EF available from DowChemical Co.). Moreover, these films are sufficiently flexible even whensubstantially free of organic solvents, which may be removed withoutcompromising film properties. As such, if there is no solvent present,then there is no plasticizer in the films. PEO based films also exhibitgood resistance to tearing, little or no curling, and fast dissolutionrates when the polymer component contains appropriate levels of PEO.

To achieve the desired film properties, the level and/or molecularweight of PEO in the polymer component may be varied. Modifying the PEOcontent affects properties such as tear resistance, dissolution rate,and adhesion tendencies. Thus, one method for controlling filmproperties is to modify the PEO content. For instance, in someembodiments rapid dissolving films are desirable. By modifying thecontent of the polymer component, the desired dissolutioncharacteristics can be achieved.

In accordance with the present invention, PEO desirably ranges fromabout 20% to 100% by weight in the polymer component. In someembodiments, the amount of PEO desirably ranges from about ling to about200 mg. The hydrophilic cellulosic polymer and/or polydextrose rangesfrom about 0% to about 80% by weight, or in a ratio of up to about 4:1with the PEO, and desirably in a ratio of about 1:1.

In some embodiments, it may be desirable to vary the PEO levels topromote certain film properties. To obtain films with high tearresistance and fast dissolution rates, levels of about 50% or greater ofPEO in the polymer component are desirable. To achieve adhesionprevention, i.e., preventing the film from adhering to the roof of themouth, PEO levels of about 20% to 75% are desirable. In someembodiments, however, adhesion to the roof of the mouth may be desired,such as for administration to animals or children. In such cases, higherlevels of PEO may be employed. More specifically, structural integrityand dissolution of the film can be controlled such that the film canadhere to mucosa and be readily removed, or adhere more firmly and bedifficult to remove, depending on the intended use.

The molecular weight of the PEO may also be varied. High molecularweight PEO, such as about 4 million, may be desired to increasemucoadhesivity of the film. More desirably, the molecular weight mayrange from about 100,000 to 900,000, more desirably from about 100,000to 600,000, and most desirably from about 100,000 to 300,000. In someembodiments, it may be desirable to combine high molecular weight(600,000 to 900,000) with low molecular weight (100,000 to 300,000) PEOsin the polymer component.

For instance, certain film properties, such as fast dissolution ratesand high tear resistance, may be attained by combining small amounts ofhigh molecular weight PEOs with larger amounts of lower molecular weightPEOs. Desirably, such compositions contain about 60% or greater levelsof the lower molecular weight PEO in the PEO-blend polymer component.

To balance the properties of adhesion prevention, fast dissolution rate,and good tear resistance, desirable film compositions may include about50% to 75% low molecular weight PEO, optionally combined with a smallamount of a higher molecular weight PEO, with the remainder of thepolymer component containing a hydrophilic cellulosic polymer (HPC orHPMC) and/or polydextrose.

Controlled Release Films

The term “controlled release” is intended to mean the release of activeat a pre-selected or desired rate. This rate will vary depending uponthe application. Desirable rates include fast or immediate releaseprofiles as well as delayed, sustained or sequential release.Combinations of release patterns, such as initial spiked releasefollowed by lower levels of sustained release of active arecontemplated. Pulsed drug releases are also contemplated.

The polymers that are chosen for the films of the present invention mayalso be chosen to allow for controlled disintegration of the active.This may be achieved by providing a substantially water insoluble filmthat incorporates an active that will be released from the film overtime. This may be accomplished by incorporating a variety of differentsoluble or insoluble polymers and may also include biodegradablepolymers in combination. Alternatively, coated controlled release activeparticles may be incorporated into a readily soluble film matrix toachieve the controlled release property of the active inside thedigestive system upon consumption.

Films that provide a controlled release of the active are particularlyuseful for buccal, gingival, sublingual and vaginal applications. Thefilms of the present invention are particularly useful where mucosalmembranes or mucosal fluid is present due to their ability to readilywet and adhere to these areas.

The convenience of administering a single dose of a medication whichreleases active ingredients in a controlled fashion over an extendedperiod of time as opposed to the administration of a number of singledoses at regular intervals has long been recognized in thepharmaceutical arts. The advantage to the patient and clinician inhaving consistent and uniform blood levels of medication over anextended period of time are likewise recognized. The advantages of avariety of sustained release dosage forms are well known. However, thepreparation of a film that provides the controlled release of an activehas advantages in addition to those well-known for controlled releasetablets. For example, thin films are difficult to inadvertently aspirateand provide an increased patient compliance because they need not beswallowed like a tablet. Moreover, certain embodiments of the inventivefilms are designed to adhere to the buccal cavity and tongue, where theycontrollably dissolve. Furthermore, thin films may not be crushed in themanner of controlled release tablets which is a problem leading to abuseof drugs such as Oxycontin.

The actives employed in the present invention may be incorporated intothe film compositions of the present invention in a controlled releaseform. For example, particles of drug may be coated with polymers such asethyl cellulose or polymethacrylate, commercially available under brandnames such as Aquacoat BCD and Eudragit E-100, respectively. Solutionsof drug may also be absorbed on such polymer materials and incorporatedinto the inventive film compositions. Other components such as fats andwaxes, as well as sweeteners and/or flavors may also be employed in suchcontrolled release compositions.

The actives may be taste-masked prior to incorporation into the filmcomposition, as set forth in co-pending PCT application titled, UniformFilms For Rapid Dissolve Dosage Form Incorporating Taste-MaskingCompositions, WO/2003/030883, the entire disclosure of which isincorporated by reference herein.

Actives

When an active is introduced to the film, the amount of active per unitarea is determined by the uniform distribution of the film. For example,when the films are cut into individual dosage forms, the amount of theactive in the dosage form can be known with a great deal of accuracy.This is achieved because the amount of the active in a given area issubstantially identical to the amount of active in an area of the samedimensions in another part of the film. The accuracy in dosage isparticularly advantageous when the active is a medicament, i.e. a drug.

The active components that may be incorporated into the films of thepresent invention include, without limitation pharmaceutical andcosmetic actives, drugs, medicaments, antigens or allergens such asragweed pollen, spores, microorganisms including bacteria, seeds,mouthwash components such as chlorates or chlorites, flavors,fragrances, enzymes, preservatives, sweetening agents, colorants,spices, vitamins and combinations thereof.

A wide variety of medicaments, bioactive active substances andpharmaceutical compositions may be included in the dosage forms of thepresent invention. Examples of useful drugs include ace-inhibitors,antianginal drugs, anti-arrhythmias, anti-asthmatics,anti-cholesterolemics, analgesics, anesthetics, anti-convulsants,anti-depressants, anti-diabetic agents, anti-diarrhea preparations,antidotes, antihistamines, anti-hypertensive drugs, anti-inflammatoryagents, anti-lipid agents, anti-manics, anti-nauseants, anti-strokeagents, anti-thyroid preparations, anti-tumor drugs, anti-viral agents,acne drugs, alkaloids, amino acid preparations, anti-tussives,anti-uricemic drugs, anti-viral drugs, anabolic preparations, systemicand non-systemic anti-infective agents, anti-neoplastics,anti-parkinsonian agents, anti-rheumatic agents, appetite stimulants,biological response modifiers, blood modifiers, bone metabolismregulators, cardiovascular agents, central nervous system stimulates,cholinesterase inhibitors, contraceptives, decongestants, dietarysupplements, dopamine receptor agonists, endometriosis managementagents, enzymes, erectile dysfunction therapies, fertility agents,gastrointestinal agents, homeopathic remedies, hormones, hypercalcemiaand hypocalcemia management agents, immunomodulators,immunosuppressives, migraine preparations, motion sickness treatments,muscle relaxants, obesity management agents, osteoporosis preparations,oxytocics, parasympatholytics, parasympathomimetics, prostaglandins,psychotherapeutic agents, respiratory agents, sedatives, smokingcessation aids such as bromocryptine and nicotine, sympatholytics,tremor preparations, urinary tract agents, vasodilators, laxatives,antacids, ion exchange resins, anti-pyretics, appetite suppressants,expectorants, anti-anxiety agents, anti-ulcer agents, anti-inflammatorysubstances, coronary dilators, cerebral dilators, peripheralvasodilators, psycho-tropics, stimulants, anti-hypertensive drugs,vasoconstrictors, migraine treatments, antibiotics, tranquilizers,anti-psychotics, anti-tumor drugs, anti-coagulants, anti-thromboticdrugs, hypnotics, anti-emetics, anti-nauseants, anti-convulsants,neuromuscular drugs, hyper- and hypo-glycemic agents, thyroid andanti-thyroid preparations, diuretics, anti-spasmodics, terine relaxants,anti-obesity drugs, erythropoietic drugs, anti-asthmatics, coughsuppressants, mucolytics, DMA and genetic modifying drugs, andcombinations thereof.

Examples of medicating active ingredients contemplated for use in thepresent invention include antacids, H₂-antagonists, and analgesics. Forexample, antacid dosages can be prepared using the ingredients calciumcarbonate alone or in combination with magnesium hydroxide, and/oraluminum hydroxide. Moreover, antacids can be used in combination withH₂-antagonists.

Analgesics include opiates and opiate derivatives, such as oxycodone(available as Oxycontin®), ibuprofen, aspirin, acetaminophen, andcombinations thereof that may optionally include caffeine.

Other preferred drugs for other preferred active ingredients for use inthe present invention include anti-diarrheals such as immodium AD,antihistamines, anti-tussives, decongestants, vitamins, and breathfresheners. Suitable vitamins contemplated for use herein include anyconventionally known vitamins, such as, but not limited to. Vitamins A,B, C and E. Common drugs used alone or in combination for colds, pain,fever, cough, congestion, runny nose and allergies, such asacetaminophen, chlorpheniramine maleate, dextromethorphan,pseudoephedrine HCl and diphenhydramine may be included in the filmcompositions of the present invention.

Also contemplated for use herein are anxiolytics such as alprazolam(available as Xanax®), anti-psychotics such as clozopin (available asClozaril®) and haloperidol (available as Haldol®); non-steroidalanti-inflammatories (NSAID's) such as dicyclofenacs (available asVoltaren®) and etodolac (available as Lodine®), anti-histamines such asloratadine (available as Claritin®), astemizole (available asHismanal™), nabumetone (available as Relafen®), and Clemastine(available as Tavist®); anti-emetics such as granisetron hydrochloride(available as Kytril®) and nabilone (available as Cesamet™);bronchodilators such as Bentolin®, albuterol sulfate (available asProventil®); anti-depressants such as fluoxetine hydrochloride(available as Prozac®), sertraline hydrochloride (available as Zoloft®),and paroxtine hydrochloride (available as Paxil®); anti-migraines suchas Imigra®, ACE-inhibitors such as enalaprilat (available as Vasotec®),captopril (available as Capoten®) and lisinopril (available asZestril®); anti-Alzheimer's agents, such as nicergoline; andCa^(H)-antagonists such as nifedipine (available as Procardia® andAdalal®), and verapamil hydrochloride (available as Calan®).

Erectile dysfunction therapies include, but are not limited to, drugsfor facilitating blood flow to the penis, and for effecting autonomicnervous activities, such as increasing parasympathetic (cholinergic) anddecreasing sympathetic (adrenergic) activities. Useful non-limitingdrugs include sildenafil, such as Viagra®, tadalafils, such as Cialis®,vardenafils, apomorphines, such as Uprima®, yohimbine hydrochloridessuch as Aphrodyne®, and alprostadils such as Caverject®.

The popular H₂-antagonists which are contemplated for use in the presentinvention include cimetidine, ranitidine hydrochloride, famotidine,nizatidien, ebrotidine, mifentidine, roxatidine, pisatidine andaceroxatidine.

Active antacid ingredients include, but are not limited to, thefollowing: aluminum hydroxide, dihydroxyaluminum aminoacetate,aminoacetic acid, aluminum phosphate, dihydroxyaluminum sodiumcarbonate, bicarbonate, bismuth aluminate, bismuth carbonate, bismuthsubcarbonate, bismuth subgallate, bismuth subnitrate, bismuthsubsilysilate, calcium carbonate, calcium phosphate, citrate ion (acidor salt), amino acetic acid, hydrate magnesium aluminate sulfate,magaldrate, magnesium aluminosilicate, magnesium carbonate, magnesiumglycinate, magnesium hydroxide, magnesium oxide, magnesium trisilicate,milk solids, aluminum mono-ordibasic calcium phosphate, tricalciumphosphate, potassium bicarbonate, sodium tartrate, sodium bicarbonate,magnesium aluminosilicates, tartaric acids and salts.

The pharmaceutically active agents employed in the present invention mayinclude allergens or antigens, such as, but not limited to, plantpollens from grasses, trees, or ragweed; animal danders, which are tinyscales shed from the skin and hair of cats and other furred animals;insects, such as house dust mites, bees, and wasps; and drugs, such aspenicillin.

Botanicals, herbals and minerals also may be added to the film. Examplesof botanicals include, without limitation: roots; barks; leaves; stems;flowers; fruits; tobacco; sunflower seeds; snuff; and combinationsthereof.

An anti-oxidant may also be added to the film to prevent the degradationof an active, especially where the active is photosensitive.

The bioactive active substances employed in the present invention mayinclude beneficial bacteria. More specifically, certain bacterianormally exist on the surface of the tongue and in the back of thethroat. Such bacteria assist in the digestion of food by breaking downproteins found in the food. It may be desirable, therefore, toincorporate these bacteria into the oral film products of the presentinvention.

It also may be desirable to include actives for treating breath malodorand related oral care conditions, such as actives which are effective insuppressing microorganisms. Because breath malodor can be caused by thepresence of anaerobic bacteria in the oral cavity, which generatevolatile sulfur compounds, components that suppress such microorganismsmay be desirable. Examples of such components include antimicrobialssuch as triclosan, chlorine dioxide, chlorates, and chlorites, amongothers. The use of chlorites, particularly sodium chlorite, in oral carecompositions such as month rinses and toothpastes is taught in U.S. Pat.Nos. 6,251,372, 6,132,702, 6,077,502, and 6,696,047, all of which areincorporated herein by reference. Such components are incorporated, inamounts effective to treat malodor and related oral conditions.

Cosmetic active agents may include breath freshening compounds likementhol, other flavors or fragrances, especially those used for oralhygiene, as well as actives used in dental and oral cleansing such asquaternary ammonium bases. The effect of flavors may be enhanced usingflavor enhancers like tartaric acid, citric acid, vanillin, or the like.

Also color additives can be used in preparing the films. Such coloradditives include food, drug and cosmetic colors (FD&C), drug andcosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C).These colors are dyes, their corresponding lakes, and certain naturaland derived colorants. Lakes are dyes absorbed on aluminum hydroxide.

Other examples of coloring agents include known azo dyes, organic orinorganic pigments, or coloring agents of natural origin. Inorganicpigments are preferred, such as the oxides or iron or titanium, theseoxides, being added in concentrations ranging from about 0.001 to about10%, and preferably about 0.5 to about 3%, based on the weight of allthe components.

Flavors may be chosen from natural and synthetic flavoring liquids. Anillustrative list of such agents includes volatile oils, syntheticflavor oils, flavoring aromatics, oils, liquids, oleoresins or extractsderived from plants, leaves, flowers, fruits, stems and combinationsthereof.

The films containing flavorings may be added to provide a hot or coldflavored drink or soup. These flavorings include, without limitation,tea and soup flavorings such as beef and chicken.

Other useful flavorings include aldehydes and esters such asbenzaldehyde (cherry, almond), citral i.e., alphacitral (lemon, lime),neral, i.e., beta-citral (lemon, lime), decanal (orange, lemon),aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehydeC-12 (citrus fruits), tolyl aldehyde (cherry, almond),2,6-dimethyloctanol (green fruit), and 2-dodecenal (citrus, mandarin),combinations thereof and the like.

The sweeteners may be chosen from the following non-limiting list:glucose (corn syrup), dextrose, invert sugar, fructose, and combinationsthereof; saccharin and its various salts such as the sodium salt;dipeptide sweeteners such as aspartame: dihydrochalcone compounds,glycyrrhizin; Stevia Rebaudiana (Stevioside); chloro derivatives ofsucrose such as sucralose; sugar alcohols such as sorbitol mannitol,xylitol, and the like. Also contemplated are hydrogenated starchhydrolysates and the synthetic sweetener3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-one-2,2-dioxide,particularly the potassium salt (acesulfame-K), and sodium and calciumsalts thereof, and natural intensive sweeteners, such as Lo Han Kuo.Other sweeteners may also be used.

When the active is combined with the polymer in the solvent, the type ofmatrix that is formed depends on the solubilities of the active and thepolymer. If the active and/or polymer are soluble in the selectedsolvent, this may form a solution. However, if the components are notsoluble, the matrix may be classified as an emulsion, a colloid, or asuspension.

Dosages

The film products of the present invention are capable of accommodatinga wide range of amounts of the active ingredient. The films are capableof providing an accurate dosage amount (determined by the size of thefilm and concentration of the active in the original polymer/watercombination) regardless of whether the required dosage is high orextremely low. Therefore, depending on the type of active orpharmaceutical composition that is incorporated into the film, theactive amount may be as high as about 300 mg, desirably up to about 150mg or as low as the microgram range, or any amount therebetween.

The film products and methods of the present invention are well suitedfor high potency, low dosage drugs. This is accomplished through thehigh degree of uniformity of the films. Therefore, low dosage drugs,particularly more potent racemic mixtures of actives are desirable.

Foam Reducing Flavoring Agents

The film of the present invention also includes at least one foamreducing flavoring agent. A foam reducing flavoring agent as definedherein is a component that can act to both flavor the film and preventand/or remove air, such as entrapped air, from the film-formingcompositions.

The foam reducing flavoring agent is added instead of traditionalanti-foaming or defoaming agents. Thus, the film of the presentinvention is free of added anti-foaming or defoaming agents.

The term “defoaming agents” is typically used to describe agents thatreduce foam after it has already formed. The term “anti-foaming agents”is typically used to describe agents that prevent foam from formingduring processing. For the purposes of this application, the terms areused interchangeably.

Conventional defoaming/anti-foaming agents are well known in the art.See, for example, McCutcheons Functional Materials, North AmericanEdition/International Edition 2005 Annuals Volume 2, The ManufacturingConfectioner Publishing Co., “Defoamers,” pp. 103-126 (2005),incorporated herein by reference. Many anti-foaming/defoaming agents aresilicone or oil based. Simethicone is one well knownanti-foaming/defoaming agent.

In order to prevent the formation of air bubbles in the films of thepresent invention, the mixing step can be performed under vacuum.However, as soon as the mixing step is completed, and the film solutionis returned to the normal atmosphere condition, air will bere-introduced into or contacted with the mixture. In many cases, tinyair bubbles will be again trapped inside this polymeric viscoussolution. The incorporation of a foam reducing flavoring agent into thefilm-forming composition either substantially reduces or eliminates theformation of air bubbles.

Flavor agents are typically added after mixing because mixing undervacuum can cause a decrease in the effect of certain flavors. However,since the foam reducing flavoring agent is used not only to flavor thefilm, but to also reduce foam, the foam reducing flavoring agent ispreferably added before mixing the other ingredients in the film-formingsolution. In this way the foam reducing flavoring agent can both preventthe formation of foam and help eliminate any foam that is formed, i.e.,act as both an anti-foam agent and a defoaming agent.

In a preferred embodiment, the foam reducing flavoring agents are fruitor aromatic or hark based. For example, the foam reducing flavoringagent can be a mint-type flavor. Suitable mint-type flavors includementhol, cinnamint, spearmint, peppermint, and combinations thereof.Natural raspberry and orange flavor, such as Orange Burst flavorAN24334582 by Noville, are also a suitable foam reducing flavoringagents. The foam reducing flavoring agents can themselves be flavored.For example, instead of menthol, the foam reducing flavoring agent canbe cherry menthol. Other variations are possible.

In a preferred embodiment, the foam reducing flavoring agent has 8 to 12carbon atoms, more preferably 10 carbon atoms. In another preferredembodiment, the foam reducing flavoring agents contain at least oneterminal dimethyl group and a non-terminal OH group. Without being boundby theory, it is believed that foam reducing flavoring agents with thesechemical groups may have an effect in interacting with the air bubblesand releasing the air entrapped therein.

Foam reducing flavoring agents generally are present in any amounteffective for the agent to both flavor the film and reduce the amount offoam produced when the film is being manufactured. For example, foamreducing flavoring agent may be present in an amount of at least 0.1%,preferably at least about 0.15%, more preferably at least about 0.5%,most preferably at least about 1.0% by weight of the film. In addition,the foam reducing flavoring agent may be present, for example, in anamount of at most 20%, preferably at most 1.5%, more preferably at most10%, most preferably at most 5% by weight of the film.

Optional Components

A variety of other components and fillers may also be added to the filmsof the present invention. These may include, without limitation,surfactants; plasticizers which assist in compatibilizing the componentswithin the mixture; polyalcohols; and thermo-setting gels such aspectin, carageenan, and gelatin, which help in maintaining thedispersion of components. Some surfactants can act asantifoam/deafoaming agents if they have a low hydrophile-lipophilebalance (“HLB”), i.e., less than 5 HLB. Therefore, the surfactants thatcan be added to the films of the present invention are surfactants thatare not intended for an antifoam/defoaming purpose, i.e., thosesurfactants that have an HLP greater than 5. Accordingly, “surfactant”as defined herein is intended to mean those surfactants not suitable asan antifoaming/defoaming agent.

The variety of additives that can be incorporated into the inventivecompositions may provide a variety of different functions. Examples ofclasses of additives include excipients, lubricants, buffering agents,stabilizers, blowing agents, pigments, coloring agents, fillers, bulkingagents, sweetening agents, flavoring agents, fragrances, releasemodifiers, adjuvants, plasticizers, flow accelerators, mold releaseagents, polyols, granulating agents, diluents, binders, buffers,absorbents, glidants, adhesives, anti-adherents, acidulants, softeners,resins, demulcents, solvents, surfactants, emulsifiers, elastomers andmixtures thereof. Such additives are known in the art (Again, as withsurfactants, none of these additives are intended to include additivesthat act as an antifoaming/defoaming agent.) These additives may beadded with the active ingredient(s).

Forming the Film

The films of the present invention must be formed into a sheet prior todrying. After the desired components are combined to form amulti-component matrix, including the polymer, water, and an active orother components as desired, the combination is formed into a sheet orfilm, by any method known in the art such as extrusion, coating,spreading, casting or drawing the multi-component matrix. If amulti-layered film is desired, this may be accomplished by co-extrudingmore than one combination of components which may be of the same ordifferent composition. A multi-layered film may also be achieved bycoating, spreading, or casting a combination onto an already formed filmlayer.

Although a variety of different film-forming techniques may be used, itis desirable to select a method that will provide a flexible film, suchas reverse roll coating. The flexibility of the film allows for thesheets of film to be rolled and transported for storage or prior tobeing cut into individual dosage forms. Desirably, the films will alsobe self-supporting or in other words able to maintain their integrityand structure in the absence of a separate support. Furthermore, thefilms of the present invention may be selected of materials that areedible or ingestible.

Coating or casting methods are particularly useful for the purpose offorming the films of the present invention. Specific examples includereverse roll coating, gravure coating, immersion or dip coating,metering rod or meyer bar coating, slot die or extrusion coating, gap orknife over roll coating, air knife coating, curtain coating, orcombinations thereof, especially when a multi-layered film is desired.

Roll coating, or more specifically reverse roll coating, is particularlydesired when forming films in accordance with the present invention.This procedure provides excellent control and uniformity of theresulting films, which is desired in the present invention. In thisprocedure, the coating material is measured onto the applicator rollerby the precision setting of the gap between the upper metering rollerand the application roller below it. The coating is transferred from theapplication roller to the substrate as it passes around the supportroller adjacent to the application roller. Both three roll and four rollprocesses are common.

The gravure coating process relies on an engraved roller running in acoating bath, which fills the engraved dots or lines of the roller withthe coating material. The excess coating on the roller is wiped off by adoctor blade and the coating is then deposited onto the substrate as itpasses between the engraved roller and a pressure roller.

Offset Gravure is common, where the coating is deposited on anintermediate roller before transfer to the substrate.

In the simple process of immersion or dip coating the substrate isdipped into a bath of the coating, which is normally of a low viscosityto enable the coating to run back into the bath as the substrateemerges.

In the metering rod coating process, an excess of the coating isdeposited onto the substrate as it passes over the bath roller. Thewire-wound metering rod, sometimes known as a Meyer Bar, allows thedesired quantity of the coating to remain on the substrate. The quantityis determined by the diameter of the wire used on the rod.

In the slot die process, the coating is squeezed out by gravity or underpressure through a slot and onto the substrate. If the coating is 100%solids, the process is termed “Extrusion” and in this case, the linespeed is frequently much faster than the speed of the extrusion. Thisenables coatings to be considerably thinner than the width of the slot.

It may be particularly desirable to employ extrusion methods for formingfilm compositions containing PEO polymer components. These compositionscontain PEO or PEO blends in the polymer component, and may beessentially free of added plasticizers, and/or surfactants, andpolyalcohols. The compositions may be extruded as a sheet at processingtemperatures of less than about 90° C. Extrusion may proceed bysqueezing the film composition through rollers or a die to obtain auniform matrix. The extruded film composition then is cooled by anymechanism known to those of ordinary skill in the art. For example,chill rollers, air cooling beds, or water cooling beds may be employed.The cooling step is particularly desirable for these film compositionsbecause PEO tends to hold heat.

The gap or knife over roll process relies on a coating being applied tothe substrate which then passes through a “gap” between a “knife” and asupport roller. As the coating and substrate pass through, the excess isscraped off.

Air knife coating is where the coating is applied to the substrate andthe excess is “blown off” by a powerful jet from the air knife. Thisprocedure is useful for aqueous coatings.

In the curtain coating process, a bath with a slot in the base allows acontinuous curtain of the coating to fall into the gap between twoconveyors. The object to be coated is passed along the conveyor at acontrolled speed and so receives the coating on its upper face.

Prying the Film

The drying step is also a contributing factor with regard to maintainingthe uniformity of the film composition. A controlled drying process isparticularly important when, in the absence of a viscosity increasingcomposition or a composition in which the viscosity is controlled, forexample by the selection of the polymer, the components within the filmmay have an increased tendency to aggregate or conglomerate. Analternative method of forming a film with an accurate dosage, that wouldnot necessitate the controlled drying process, would be to cast thefilms on a predetermined well. With this method, although the componentsmay aggregate, this will not result in the migration of the active to anadjacent dosage form, since each well may define the dosage unit per se.

When a controlled or rapid drying process is desired, this may bethrough a variety of methods. A variety of methods may be used includingthose that require the application of heat. The liquid carriers areremoved from the film in a manner such that the uniformity, or morespecifically, the non-self-aggregating uniform heterogeneity, that isobtained in the wet film is maintained.

Desirably, the film is dried from the bottom of the film to the top ofthe film. Desirably, substantially no air flow is present across the topof the film during its initial setting period, during which a solid,visco-elastic structure is formed. This can take place within the firstfew minutes, e.g. about the first 0.5 to about 4.0 minutes of the dryingprocess. Controlling the drying in this manner, prevents the destructionand reformation of the film's top surface, which results fromconventional drying methods. This is accomplished by forming the filmand placing it on the top side of a surface having top and bottom sides.Then, heat is initially applied to the bottom side of the film toprovide the necessary energy to evaporate or otherwise remove the liquidcarrier. The films dried in this manner dry more quickly and evenly ascompared to air-dried films, or those dried by conventional dryingmeans. In contrast to an air-dried film that dries first at the top andedges, the films dried by applying heat to the bottom dry simultaneouslyat the center as well as at the edges. This also prevents settling ofingredients that occurs with films dried by conventional means.

The temperature at which the films are dried is about 100° C. or less,desirably about 90° C. or less, and most desirably about 80° C. or less.

In some embodiments, the weight of the polar solvent is at least about30% of the film before drying. In some other embodiments, the drying ofthe film reduces the weight percent of the polar solvent to about 10% orless. Preferably, the drying occurs within about 10 minutes or fewer.

Another method of controlling the drying process, which may be usedalone or in combination with other controlled methods as disclosed aboveincludes controlling and modifying the humidity within the dryingapparatus where the film is being dried. In this manner, the prematuredrying of the top surface of the film is avoided.

Additionally, it has also been discovered that the length of drying timecan be properly controlled, i.e. balanced with the heat sensitivity andvolatility of the components, and particularly the flavor oils anddrugs. The amount of energy, temperature and length and speed of theconveyor can be balanced to accommodate such actives and to minimizeloss, degradation or ineffectiveness in the final film.

A specific example of an appropriate drying method is that disclosed byMagoon. Magoon is specifically directed toward a method of drying fruitpulp. However, the present inventors have adapted this process towardthe preparation of thin films.

The method and apparatus of Magoon are based on an interesting propertyof water. Although water transmits energy by conduction and convectionboth within and to its surroundings, water only radiates energy withinand to water. Therefore, the apparatus of Magoon includes a surface ontowhich the fruit pulp is placed that is transparent to infraredradiation. The underside of the surface is in contact with a temperaturecontrolled water bath. The water bath temperature is desirablycontrolled at a temperature slightly below the boiling temperature ofwater. When the wet fruit pulp is placed on the surface of theapparatus, this creates a “refractance window.” This means that infraredenergy is permitted to radiate through the surface only to the area onthe surface occupied by the fruit pulp, and only until the fruit pulp isdry. The apparatus of Magoon provides the films of the present inventionwith an efficient drying time reducing the instance of aggregation ofthe components of the film.

Another method of controlling the drying process involves a zone dryingprocedure. A zone drying apparatus may include a continuous belt dryingtunnel having one or more drying zones located within. The conditions ofeach drying zone may vary, for example, temperature and humidity may beselectively chosen. It may be desirable to sequentially order the zonesto provide a stepped up drying effect.

The speed of the zone drying conveyor desirably is continuous.Alternatively, the speed may be altered at a particular stage of thedrying procedure to increase or decrease exposure of the film to theconditions of the desired zone. Whether continuous or modified, the zonedrying dries the film without surface skinning.

According to an embodiment of the zone drying apparatus 100, shown inFIG. 9, the film 110 may be fed onto the continuous belt 120, whichcarries the film through the different drying zones. The first dryingzone that the film travels through 101 may be a warm and humid zone. Thesecond zone 102 may be hotter and drier, and the third zone 103 may alsobe hot and dry. These different zones may be continuous, oralternatively, they may be separated, as depicted by the zone dryingapparatus 200 in FIG. 10, where the first drying zone 201, second dryingzone 202 and third drying zone 203 are shown. The zone drying apparatus,in accordance with the present invention, is not limited to three dryingzones. The film may travel through lesser or additional drying zones ofvarying heat and humidity levels, if desired, to produce the controlleddrying effect of the present invention.

To further control temperature and humidity, the drying zones mayinclude additional atmospheric conditions, such as inert gases. The zonedrying apparatus further may be adapted to include additional processesduring the zone drying procedure, such as, for example, spraying andlaminating processes, so long as controlled drying is maintained inaccordance with the invention.

The films may initially have a thickness of about 500 μm to about 1,500μm, or about 20 mils to about 60 mils, and when dried have a thicknessfrom about 3 μm to about 250 μm, or about 0.1 mils to about 10 mils. Insome embodiments, the film product has a thickness of greater than 0.1mils. In some other embodiments, the film product has a thickness ofabout 10 mils or fewer. In some further embodiments, the film producthas a thickness of about 0.5 mils to about 5 mils. Desirably, the driedfilms will have a thickness of about 2 mils to about 8 mils, and moredesirably, from about 3 mils to about 6 mils.

Testing Films for Uniformity

If may be desirable to test the films of the present invention forchemical and physical uniformity during the film manufacturing process.In particular, samples of the film may be removed and tested foruniformity in film components between various samples. Film thicknessand over all appearance may also be checked for uniformity. Uniformfilms are desired, particularly for films containing pharmaceuticalactive components for safety and efficacy reasons.

A method for testing uniformity in accordance with the present inventionincludes conveying a film through a manufacturing process. This processmay include subjecting the film to drying processes, dividing the filminto individual dosage units, and/or packaging the dosages, amongothers. As the film is conveyed through the manufacturing process, forexample on a conveyor belt apparatus, it is cut width wise into at leastone portion. The at least one portion has opposing ends that areseparate from any other film portion. For instance, if the film is aroll, it may be cut into separate sub-rolls. Cutting the film may beaccomplished by a variety of methods, such as with a knife, razor,laser, or any other suitable means for cutting a film.

The cut film then may be sampled by removing small pieces from each ofthe opposed ends of the portion(s), without disrupting the middle of theportion(s). Leaving the middle section intact permits the predominantportion of the film to proceed through the manufacturing process withoutinterrupting the conformity of the film and creating sample-inductedgaps in the film. Accordingly, the concern of missing doses isalleviated as the film is further processed, e.g., packaged. Moreover,maintaining the completeness of cut portions or sub-rolls throughout theprocess will help to alleviate the possibility of interruptions infurther film processing or packaging due to guilty control issues, forexample, alarm stoppage due to notice of missing pieces.

After the end pieces, or sampling sections, are removed from the filmportion(s), they may be tested for uniformity in the content ofcomponents between samples. Any conventional means for examining andtesting the film pieces may be employed, such as, for example, visualinspection, use of analytical equipment, and any other suitable meansknown to those skilled in the art. If the testing results shownon-uniformity between film samples, the manufacturing process may bealtered. This can save time and expense because the process may bealtered prior to completing an entire manufacturing run. For example,the drying conditions, mixing conditions, compositional componentsand/or film viscosity may be changed. Altering the drying conditions mayinvolve changing the temperature, drying time, moisture level, and dryerpositioning, among others.

Moreover, it may be desirable to repeat the steps of sampling andtesting throughout the manufacturing process. Testing at multipleintervals may ensure that uniform film dosages are continuouslyproduced. Alterations to the process can be implemented at any stage tominimize non-uniformity between samples.

Uses of Thin Films

The thin films of the present invention are well suited for many uses.The high degree of uniformity of the components of the film makes themparticularly well suited for incorporating pharmaceuticals. Furthermore,the polymers used in construction of the films may be chosen to allowfor a range of disintegration tunes for the films. A variation orextension in the time over which a film will disintegrate may achievecontrol over the rate that the active is released, which may allow for asustained release delivery system. In addition, the films may be usedfor the administration of an active to any of several body surfaces,especially those including mucous membranes, such as oral, anal,vaginal, ophthalmological, the surface of a wound, either on a skinsurface or within a body such as during surgery, and similar surfaces.

The films may be used to orally administer an active. This isaccomplished by preparing the films as described above and introducingthem to the oral cavity of a mammal. This film may be prepared andadhered to a second or support layer from which it is removed prior touse, i.e. introduction to the oral cavity. An adhesive may be used toattach the film to the support or backing material which may be any ofthose known in the art, and is preferably not water soluble. If anadhesive is used, it will desirably be a food grade adhesive that isingestible and does not alter the properties of the active. Mucoadhesivecompositions are particularly useful. The film compositions in manycases serve as mucoadhesives themselves.

The films may be applied under or to the tongue of the mammal. When thisis desired, a specific film shape, corresponding to the shape of thetongue may be preferred. Therefore the film may be cut to a shape wherethe side of the film corresponding to the back of the tongue will belonger than the side corresponding to the front of the tongue.Specifically, the desired shape may be that of a triangle or trapezoid.Desirably, the film will adhere to the oral cavity preventing it frombeing ejected from the oral cavity and permitting more of the active tobe introduced to the oral cavity as the film dissolves.

Another use for the films of the present invention takes advantage ofthe films' tendency to dissolve quickly when introduce to a liquid. Anactive may be introduced to a liquid by preparing a film in accordancewith the present invention, introducing it to a liquid, and allowing itto dissolve. This may be used either to prepare a liquid dosage form ofan active, or to flavor a beverage.

The films of the present invention are desirably packaged in sealed, airand moisture resistant packages to protect the active from exposureoxidation, hydrolysis, volatilization and interaction with theenvironment. Referring to FIG. 1, a packaged pharmaceutical dosage unit10, includes each film 12 individually wrapped in a pouch or betweenfoil and/or plastic laminate sheets 14. As depicted in FIG. 2, thepouches 10, 10′ can be linked together with tearable or perforatedjoints 16. The pouches 10, 10′ may be packaged in a roll as depicted inFIG. 5 or stacked as shown in FIG. 3 and sold in a dispenser 18 as shownin FIG. 4. The dispenser may contain a full supply of the medicationtypically prescribed for the intended therapy, but due to the thinnessof the film and package, is smaller and more convenient than traditionalbottles used for tablets, capsules and liquids. Moreover, the films ofthe present invention dissolve instantly upon contact with saliva ormucosal membrane areas, eliminating the need to wash the dose down withwater.

Desirably, a series of such unit doses are packaged together inaccordance with the prescribed regimen or treatment, e.g., a 10-90 daysupply, depending on the particular therapy. The individual films can bepackaged on a backing and peeled off for use.

The features and advantages of the present invention are more fullyshown by the following examples which are provided for purposes ofillustration, and are not to be construed as limiting the invention inany way.

EXAMPLES Example 1

Water-soluble film compositions were prepared using the components setforth in Table 1. The use of low levels of flavors as defoamers in thewater-soluble film compositions was evaluated.

TABLE 1 Component Number Amount Weight % Component 1. 24.47 g  21.96%Polyethylene oxide 2. 13.73 g  10.98% Hydroxypropyl methylcellulose (15cps) 3. 18.50 g  14.79% Polydextrose 4. 3.13 g  2.5% Sucralose¹ 5. 0.63g  0.5% Mono-ammonium glycyrrhizinate² 6. 1.25 g    1% Sodiumbicarbonate 7. 2.28 g  1.82% Magnesium stearate 8. 0.63 g  0.5%Hydrophilic titanium dioxide 9. 232.31 g  Distilled water ¹Commerciallyavailable from McNeil Nutrition ²Commercially available as Magna Sweet100 from Mafco Worldwide Corp.

Components 8 and 9 were placed in a Degussa 1300 bowl. The componentswere then processed as described below using the Degussa Dental MultivacCompact.

12 minutes stirring = 500 rpm vac. = 0%  4 minutes stirring = 150 rpmvac. = 0% after added a blend of ingredients 1, 2, 3, 4, 5, 6 & 7  1minute stirring = 100 rpm vac. = 0%

The resulting solution was foamy. 20 g of the foamy solution was thenadded to each of eight 2 ounce wide mouth jars. 0.27 g of glycerolmonooleate, a conventional defoaming agent, and the various flavorcompounds indicated below were then added to the bottles. (0.27 g wouldcorrespond to ˜4% in solids of a film).

-   -   1. Glycerol monooleate (commercially available as Aldo Mo KFG)    -   2. Soothing Mist AN143567 (Noville).    -   3. Orange Burst AN143482 (Noville).    -   4. Black Cherry SN486305 (IFF)    -   5. Strawberry SN279913 (IFF)    -   6. Natural Raspberry 188a10 (Abelei)    -   7. Cinnamint AN144390 (Noville)    -   8. Peppermint Bittermask RDW2-193A (Armtodd Co.)

The level of foaminess was then measured as a function of a decrease inthe height of the foam within the wide mouth jars. The drop in foamheight was measured for the glycerol monooleate jar. This height wasused as the measure of effectiveness of the antifoam agents and was setat 100%. Soothing Mint AN143567, Raspberry 188a10, Cinnamint AN144390,and Peppermint Bittermask RDW2-193A gave a decrease in the level of foamequivalent to glycerol monooleate. Orange Burst AN143482 was only ˜25%as effective as glycerol monooleate in reducing the foam level. BlackCherry SN486305 and Strawberry SN279913 did not yield any significantreduction in the foam level.

Example 2

Water-soluble film compositions were prepared using the components setforth in Table 2. The efficacy of a foam reducing flavoring agent wascompared to conventional defoaming agents.

TABLE 2 Component Number Amount Weight % Component 1. 27.47 g  21.96%Polyethylene oxide 2. 13.73 g  10.98% Hydroxypropyl methylcellulose (15cps) 3. 18.50 g  14.79% Polydextrose 4. 3.13 g  2.5% Sucralose ® (McNeilNutritionals) 5. 0.63 g  0.5% Mono-ammonium glycyrrhizinate³ 6. 1.25 g   1% Sodium bicarbonate 7. 2.28 g  1.82% Magnesium stearate 8. 0.63 g 0.5% Hydrophilic titanium dioxide 9. 232.31 g  Distilled Water³Commercially available as Magna Sweet 100 from Mafco Worldwide Corp.

Ingredients 8 and 9 was placed in a bowl and processed as describedbelow using the Degussa Dental Multivac Compact.

8 minutes stirring = 500 rpm vac. = 0% (using A310 impeller) 5 minutesstirring = 100 rpm vac. = 0% (using gate impeller) after added a blendof ingredients 1, 2, 3, 4, 5, 6 & 7

The resulting solution was foamy. 20 g of the foamy solution were thenadded to each of nine 2 ounce wide mouth jars. 0.27 g of the compoundsindicated below were then added to the bottles and observed.

-   -   1. Glycerol monooleate (commercially available as Aldo Mo KFG)    -   2. Miglyol® 840    -   3. Miglyol® 810    -   4. Miglyol® 829    -   5. Miglyol® 812    -   6. Miglyol® 818    -   7. Vegetable (Wesson® Canola) Oil    -   8. Isopropyl Alcohol    -   9. Vicks® Cough Drop Cherry Type F1. AN145163 Miglyol® (Condea        Chemie GmbH) samples are clear neutral fatty-acid esters.

The drop in foam height was measured for the glycerol monoleate jar.This height was used as the measure of effectiveness of the antifoamagent and was set at 100%. All other jars was measured as a % of thisheight. The only compound which gave a significant decrease in level offoam was the cherry flavor. Another sample was tested in which theamount of cherry flavor added was ˜25% of that added earlier or 0.0675g. This sample also gave a significant decrease in level of foam.

Example 3

An edible water-soluble film containing dextromethorphan HBr (D_(x)) asan active ingredient was prepared using 1% cherry flavor as a defoamingagent. (92.3 mg strip contains ˜15 mg D_(x)) (35% solids) The componentsused to form the film are set forth in Table 3.

TABLE 3 Component Number Amount Weight % Component 1. 3.84 g 21.96% Polyethylene oxide 2. 1.92 g 10.98%  Hydroxypropyl methylcellulose (15cps) 3. 2.59 g 14.79 Polydextrose 4. 0.44 g 2.5% Sucralose ® (McNeilNutritionals) 5. 0.09 g 0.5% Mono-ammonium glycyrrhizinate⁴ 6. 0.17 g  1% Sodium bicarbonate 7. 0.32 g 1.82%  Magnesium stearate 8. 5.47 g31.25%  D_(x) (52% w/w) 640A 040702W 101-01 (Coating Place, Inc.) 9.2.29 g 13.05%  Vicks ® Cough Drop Cherry Type Fl. AN145163 (Noville) 10.0.017 g  0.1% Butylated hydroxytoluene (Spectrum Chemicals) 11. 0.079 g 0.45%  Cyclohexanecarboximide⁵ 12. 0.17 g   1% Vicks ® Cough Drop CherryType Fl. AN145163 (Noville) 13. 0.017 g  0.1% FD&C Red #40 14. 0.09 g0.5% Hydrophilic titanium dioxide 15. 32.5 g Distilled water⁴Commercially available as Magna Sweet ® 100 from Mafco Worldwide Corp.⁵Acts as a coolant and is commercially available as WS-3 ® fromMillennium Chem.

Ingredients 12, 13, 14 and 15 were added to a Degussa 1100 bowl. Thesolution was then processed as described below using the DegussaMultivac Compact.

12 minutes  stirring = 250 rpm vac. = 0% 20 minutes  stirring = 100 rpmvac. = 50% (13 in Hg) after added a blend of components 1, 2, 3, 4, 5, 6& 7 4 minutes stirring = 100 rpm vac. = 60% (17.5 in Hg) 4 minutesstirring = 100 rpm vac. = 65% (19.5 in Hg) 12 minutes  stirring = 100rpm vac. = 70% (20.5 in Hg) 20 minutes  stirring = 100 rpm vac. = 75%(21.5 in Hg) 4 minutes stirring = 150 rpm vac. = 90% (24.5 in Hg) afteradded a solution compound of 9, 10, & 11 (heated initially at 80° C.) 4minutes stirring = 150 rpm vac. = 100% (27 in Hg) 4 minutes stirring =100 rpm vac. = 100% (27 in Hg) after added ingredient 8

The solution was cast into film using the K-control coater with themicrometer adjustable wedge bar set at 530 microns onto 55# ps/l/s “IN”release paper (Griff). The film was dried 17 minutes in an 80° C. airoven. Air moisture was 3.87% as measured by a moisture analyzer (HR73,Mettler Toledo). The film was cut into 23 mm×33.9 mm strips whichweighed ˜86-98 mg.

The film had no mottling, had good taste, and had no bitterness. The 1%cherry flavor worked well as a defoaming agent.

Thus, while there have been described what are presently believed to bethe preferred embodiments of the invention, those skilled in the artwill realize that changes and modifications can be made thereto withoutdeparting from the spirit of the invention, and it is intended to claimall such changes and modifications which fall within the true scope ofthe invention.

1. A method of preparing an edible water-soluble film composition, saidmethod comprising: a) preparing a master batch of film-formingcomponents comprising a water-soluble polymer, a foam reducing flavoringagent selected from the group consisting of menthol, cherry menthol,cinnamint, spearmint, peppermint, orange flavor, natural raspberry, andcombinations thereof, and a polar solvent, wherein said foam reducingflavoring agent is added before mixing said polymer with said solvent;b) mixing said film-forming components under vacuum; c) wet casting saidfilm-forming components; and d) removing said polar solvent through acontrolled drying process to form said edible water-soluble film;wherein said film is free of added defoaming agents.
 2. The method ofclaim 1, wherein the foam reducing flavoring agent is present in amountof about 0.1% to about 20% by weight of the film.
 3. The method of claim1, wherein the foam reducing flavoring agent is present in amount ofabout 0.5% to about 15% by weight of the film.
 4. The method of claim 1,wherein said film composition further comprises an active agent.
 5. Themethod of claim 1, wherein said foam reducing flavoring agent comprisesmenthol.